Structure of ClfA002 in Complex With Neutralizing Antibody AZD7745 Provides Insight into Its Broad Neutralization...

Area of Science:

• Microbiology and Immunology
• Infectious Diseases
• Therapeutic Development

Background:

• Staphylococcus aureus infections pose significant health risks due to limited treatment options.
• Current therapies for S. aureus infections lack broad strain coverage.
• Developing a broad neutralizing therapy is crucial for combating S. aureus.

Purpose of the Study:

• To determine the epitope of AZD7745, a monoclonal antibody targeting clumping factor A (ClfA).
• To assess the conservation of the AZD7745 epitope across a global collection of S. aureus bacteremia isolates.
• To evaluate the neutralizing activity of AZD7745 against various ClfA subtypes.

Main Methods:

• Determined AZD7745 epitope via cocrystal structure of AZD7745 Fab with ClfA N2N3 domain.
• Collected and whole-genome sequenced 174 geographically diverse S. aureus bacteremia isolates (2022-2023).
• Assessed in-vitro neutralizing activity of AZD7745 against ClfA variants using a fibrinogen/ClfA binding assay.

Main Results:

• Identified 12 binding residues on the ClfA N3 domain as the AZD7745 epitope.
• Found 45 ClfA subtypes among isolates, with 29 variations on contact residues.
• Demonstrated AZD7745 neutralized all tested ClfA subtypes by preventing fibrinogen binding through conformational changes.

Conclusions:

• Clumping factor A (ClfA) is widely present in global S. aureus clinical isolates.
• The AZD7745 epitope on ClfA is highly conserved across these isolates.
• AZD7745 shows potential for broad coverage against Staphylococcus aureus infections.